Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, MD 20892-9415, USA.
Bioorg Med Chem. 2011 Jul 15;19(14):4330-7. doi: 10.1016/j.bmc.2011.05.035. Epub 2011 May 24.
N-Phenethyl-substituted ortho-a and para-a oxide-bridged phenylmorphans have been obtained through an improved synthesis and their binding affinity examined at the various opioid receptors. Although the N-phenethyl substituent showed much greater affinity for μ- and κ-opioid receptors than their N-methyl relatives (e.g., K(i)=167 nM and 171 nM at μ- and κ-receptors vs >2800 and 7500 nM for the N-methyl ortho-a oxide-bridged phenylmorphan), the a-isomers were not examined further because of their relatively low affinity. The N-phenethyl substituted ortho-b and para-b oxide-bridged phenylmorphans were also synthesized and their enantiomers were obtained using supercritical fluid chromatography. Of the four enantiomers, only the (+)-ortho-b isomer had moderate affinity for μ- and κ-receptors (K(i)=49 and 42 nM, respectively, and it was found to also have moderate μ- and κ-opioid antagonist activity in the [(35)S]GTP-γ-S assay (K(e)=31 and 26 nM).
N-苯乙基取代的邻位-a 和对位-a 氧化物桥联苯并吗啡烷通过改进的合成方法得到，并在各种阿片受体中检测了它们的结合亲和力。尽管 N-苯乙基取代基对 μ-和 κ-阿片受体的亲和力比其 N-甲基类似物强得多（例如，在 μ-和 κ-受体中，K(i)值分别为 167 nM 和 171 nM，而 N-甲基邻位-a 氧化物桥联苯并吗啡烷的 K(i)值分别为>2800 nM 和 7500 nM），但由于其亲和力相对较低，因此未进一步研究 a-异构体。还合成了 N-苯乙基取代的邻位-b 和对位-b 氧化物桥联苯并吗啡烷，并使用超临界流体色谱获得了它们的对映异构体。在这四个对映异构体中，只有 (+)-邻位-b 异构体对 μ-和 κ-受体具有中等亲和力（K(i)值分别为 49 和 42 nM，并且在 [(35)S]GTP-γ-S 测定中也发现其具有中等 μ-和 κ-阿片受体拮抗剂活性（K(e)值分别为 31 和 26 nM）。
